Glaucoma is a degenerative disease of the eye comprising a group of eye diseases, usually associated with an increase in intraocular pressure due to an imbalance in aqueous humor dynamics. Open-angle glaucoma is the most common form of glaucoma in the western world and is characterized by deficient drainage of aqueous humor, and normal or increased intraocular pressure (IOP). The pathological changes that occur in the optic nerve head, the optic disk (degeneration of the retinal ganglion cells) result in loss of vision and eventual blindness.
Many of the drugs formerly used to treat glaucoma proved unsatisfactory. Early methods of treating glaucoma employed pilocarpine, a non-selective muscarinic agonist, and/or epinephrine. These agents decrease resistance to aqueous humor flow in the traecular meshwork outflow channels that represent 85 to 90% of aqueous outflow in the eye. However, pilocarpine and epinephrine produce undesirable local effects that made these drugs, though valuable, unsatisfactory as a first line drug. For a discussion on m1 receptor agonists see D. W. Gil, et al., Invest-Ophthalmol, Vis. Sci. 1997 June; 38(7): 1434-42; J. S. Ward et al., J. Med. Chem. 1998 Jan. 29; 41(3): 379-92; Sauerbert, et al., Bioorg. Med. Chem Let. 1998, 8: 2897-2902; and L. Jeppesen, J. Med. Chem. 1999 June 3; 42(11): 1999-2006.
More recently, clinicians have noted that many β-adrenergic antagonists are effective in reducing intraocular pressure. While many of these agents are effective for this purpose, there exist some patients in whom this treatment is not effective or not sufficiently effective. Many of these agents also have other characteristics, e.g., membrane stabilizing activity, that become more apparent with increased doses and render them unacceptable for chronic ocular use and can also cause cardiovascular effects. Alpha2 adrenergic receptor agonists such as clonidine and brimonidine are also agents used to treat elevated IOP.
Agents referred to as carbonic anhydrase inhibitors are also used to treat elevated IOP. They do so by decreasing the formation of aqueous humor by inhibiting the enzyme carbonic anhydrase. While such carbonic anhydrase inhibitors are now used to treat intraocular pressure by systemic and topical routes, current therapies using these agents, particularly those using systemic routes are still not without undesirable effects. Because carbonic anhydrase inhibitors have a profound effect in altering basic physiological processes, the avoidance of a systemic route of administration serves to diminish, if not entirely eliminate, those side effects caused by inhibition of carbonic anhydrase such as metabolic acidosis, vomiting, numbness, tingling, general malaise and the like. Topically effective carbonic anhydrase inhibitors are disclosed in U.S. Pat. Nos. 4,386,098; 4,416,890; 4,426,388; 4,668,697; 4,863,922; 4,797,413; 5,378,703, 5,240,923 and 5,153,192.
Prostaglandins and prostaglandin derivatives are also known to lower intraocular pressure. U.S. Pat. No. 4,883,819 to Bito describes the use and synthesis of PGAs, PGBs and POCs in reducing intraocular pressure. U.S. Pat. No. 4,824,857 to Goh et al. describes the use and synthesis of PGD2 and derivatives thereof in lowering intraocular pressure including derivatives wherein C-10 is replaced with nitrogen. U.S. Pat. No. 5,001,153 to Ueno et al. describes the use and synthesis of 13,14-dihydro-15-keto prostaglandins and prostaglandin derivatives to lower intraocular pressure. U.S. Pat. No. 4,599,353 describes the use of eicosanoids and eicosanoid derivatives including prostaglandins and prostaglandin inhibitors in lowering intraocular pressure.
Prostaglandin and prostaglandin derivatives lower intraocular pressure by increasing uveoscleral outflow. This is true for both the F type and A type of PGs and hence presumably also for the B, C, D, E and J types of prostaglandins and derivatives thereof. A problem with using prostaglandin derivatives to lower intraocular pressure is that these compounds often induce an initial increase in intraocular pressure, can change the color of eye pigmentation and cause proliferation of some tissues surrounding the eye.
As can be seen, there are several current therapies for treating glaucoma and elevated intraocular pressure, but the efficacy and the side effect profiles of these agents are not ideal.
Intraocular pressure is determined by the rate of aqueous humor production and the resistance to aqueous humor outflow. This invention relates to novel muscarinic agonists that are selective for m1 receptors and their use to reduce intraocular pressure in the eye and therefore provide yet one more approach to the treatment of ocular hypertension and the degenerative ocular conditions related thereto. The m1 agonists decrease resistance of the structures of the limbus, such as the trabecular meshwork. Use of the selective m1 muscarinic agonist reduces or eliminates side effects elicited by alpha2 adrenergic agonists, beta adrenergic antagonists, potassium channel blockers, and prostaglandin analogs.
This invention also relates to use of the m1 agonists for the treatment of dementia such as Alzheimer's disease and vascular dementia, depression, attention deficit disorder, sleep disorder, schizophrenia, pain, atrophic gastritis, and atony of gastrointestinal tract.
Patent publications WO 97/24324 and WO 01/30348 disclose compounds structurally related to those of the present invention as tachykinin/Substance P antagonists, but these compounds are different from this invention in their pharmacological properties and structures.
Patent publications WO 96/13262, WO 97/16192 and U.S. Pat. No. 5,756,508 also disclose compounds analogous to the present invention as muscarinic antagonists. However, these prior art publications do not teach anything about the muscarinic agonist activity at all.
Patent publications WO 99/32481, WO 01/27104, WO 97/16186 and U.S. Pat. No. 5,718,912 disclose benzimidazolidinone derivatives as muscarinic agonists. However, these publications do not claim that their compounds show a m1 selectivity, neither do they contain any specific disclosure about the compounds of the present invention.